Field of the Invention:
The present invention provides process for the preparation of N-[5-(4-bromophenyl)-
6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N,-propylsulfamide represented by the following structural formula-1.

Formula-1

The present invention also provides solid state forms of intermediate compounds of formula-1.
10

Background of the Invention:
N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-
propylsulfamide (commonly known as Macitentan) is an endothelin receptor antagonist
(ERA) approved for the treatment of pulmonary arterial hypertension (PAH).
15 US7094781B2 patent first describes N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-
pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsuifamide and broadly covers process for its preparation.
JMC, 2012, 55 (17), 7849-61 discloses process for the preparation of Macitentan and
of 20 reported the compound as a white powder with M.R. 135-136°C which is obtained bv
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crystallization from methanol.
WO2014173805A1 has characterized Macitentan obtained according to the process disclosed in above JMC, 2012, 55 (17), 7849-61 and designated the polymorph as crystalline
g form-I.

Q iio
25
o
CN
The main objective of the present invention is to provide process for the preparation
and purification of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-
g pyrimidinyl]-N'-propylsulfamide.
CO
CN CM
CN
CO
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S PAYEMT OFFICE ClrfENM-AI'' ' "1 & >S5 ^i&16 " 1 7 -2 1
3
f
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Brief description of the invention:
The first aspect of the present invention is to provide process for the preparation of
N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propyl sulfamide compound of formula-1.
5 The second aspect of the present invention is to provide process for the purification of
N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propyl sulfamide compound of formula-1.
The third aspect of the present invention is to provide novel crystalline polymorph of
N-[5-(4-bromophenyl)-6-chloro-4-pyrimidinyl]-N'-propylsulfamideofformula-4a.
10 The fourth aspect of the present invention is to provide hovel crystalline polymorph
of N-[5-(4-bromophenyl)-6-[2-hydroxyethoxy]-4-pyrimidinyl]-N,-propylsulfarriide
compound of formula-5.
The fifth aspect of the present invention is to provide process for the preparation of
5-(4-bromophenyl)-4,6-dichloropyrimidine compound of formula-2a.
15 The sixth aspect of the present invention is to provide process for the preparation of
N-propyl sulfamide compound of formula-3.
Brief Description of the Drawings:
Fjgure-1: Illustrates the PXRD pattern of crystalline form-M of N-[5-(4-bromophenyl)-6-
20 chloro-4-pyrimidinyl]-N'-propyl sulfamide compound of formula-4a.
Figure-2: Illustrates the PXRD pattern of crystalline form-N of N-[5-(4-bromophenyl)-6-[2-hydroxyethoxy] -4-pyrimidiny 1] -N'-propylsulfamide compound of formula-5. Figure-3: Illustrates the PXRD pattern of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide compound of formula-1
25 obtained according to example-7.
Detailed description of the Invention:
The term "suitable solvent" used in the present invention refers to "hydrocarbon
solvents" such as n-pentane, n-hexanes n-heptane, cyclohexane, pet ether, benzene, toluene,
30 xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether,
methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and the like;
3
PA.TEMI OFFICE CHEM^AT 15.^8^2816 17*21- ^

"ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents" such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, t-butanol, ethane-1,2-diol, propane- 1,2-diol and the like; "polar solvents" such as water; formic acid, acetic acid' or mixture of: any of the aforementioned solvents.
The term "suitable base" used in the present invention refers to "inorganic bases" selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; "alkali metal hOydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide and the like; alkali metal and alkali earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like; ammonia; "organic bases" like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, triisopropyl amine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine, imidazole, N-methylimidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), N-methyl morpholine, l,4-diazabicyclo[2.2.2]octane (DABCO), 2,6-lutidine and the like; "organolithium bases" such as methyl lithium, n-butyl lithium, lithium diisopropylamide and the like; "organosilicon bases" such as lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide and the like or their mixtures.
4

The first aspect of the present invention provides a process for the preparation of
N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propyl sulfamide compound of formula-1, comprising of; a) Reacting the compound of general formula-2

N X2
Formula-2 wherein, (Xi' & 'X2' represents leaving groups selected from halogens such as CI, Br;
alkyl/(substituted or unsubstitutedjarylsulfonyloxy groups;
i . t . . .. _ . . .
with N-propylsulfamide compound of formula-3

10
Formula-3 in presence of a suitable base in a suitable solvent to provide compound of general formula-4,

H

-Br

15
a
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u w
a
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X
o
I
CO CO CO
CM CN
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Formula-4 b) reacting the compound of general formula-4 with ethylene glycol in presence of a suitable base in a suitable solvent to provide N-[5-(4-bromophenyl)-6-[2-hydroxyethoxy]-4-pyrimidinyl]-N'-propylsulfamide compound of formula-5,
Ow>0
H
20
Formula-5 c) reacting the compound of formula-5 with 5-bromo-2-chloropyrimidine in presence of a suitable base in a suitable solvent to provide compound of formula-1,
PATEMl OFFICE CtfENNAI ■. lS/'5 8.^2tl6 1/-21

d) purifying the compound of formula-1 from a suitable solvent or mixture of solvents to provide pure compound of formula-1.
Wherein, in step-a) to step-d) wherever necessary the suitable solvent is selected from but not limited to hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents or their mixtures;
In step-a) to step-c) the suitable base is selected from but not limited to organic bases, inorganic bases, organolithium bases, organosilicon bases or their mixtures.
10
The second aspect of the present invention provides a process for the purification of N- [5 -(4-bromopheny 1) -6- [2-[(5 -bromo-2-pyrimidiny l)oxy] ethoxy] -4-pyrimidinyl] -N'-propy 1 sulfamide compound of formula-1, comprising of; a) Dissolving the compound of formula-1 in a suitable solvent, 15 b) optionally treating the reaction mixture with charcoal,
c) slowly adding a suitable anti-solvent to the solution to provide pure compound of formula-1.
Wherein, in step-a) the suitable solvent is selected from chloro solvents, cyclic ether
20 solvents, polar-aprotic solvents, ester solvents,, ketone solvents or their mixtures and in
step-c) the suitable anti-solvent is selected from alcohol solvents, polar solvents, hydrocarbon
solvents or their mixtures. The suitable solvent preferably is dichloromethane and the suitable
anti-solvent is methanol.

25 Step-c) of the above process further optionally comprises heating the reaction mixture
to a suitable temperature ranges from 30°C to 120°C and then cooling to lower temperatures
ranges from 30°C to -30°C followed by filtering and drying the solid to provide pure

CD
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compound.
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io 30 One embodiment of the present invention provides a process for the purification of
N-[5 -(4-bromophenyl)-6- [2- [(5-bromo-2-pyrimidinyl)oxy] ethoxy] -4-pyrimidinyl] -N'-propyl

sulfamide compound of formula-1, comprising of;
a) Dissolving the compound of formula-1 in dichloromethane,

b) slowly adding methanol to the reaction mixture,
c) optionally heating and cooling the reaction mixture followed by filtering to provide pure compound of formula-1.

The following impurities have been observed during the synthesis of compound of formula-1 by the process of the present invention.

Ethylene hydroxy impurity

Pyrimidine amine impurity

10



N NH H
Pyrimidine N-propyl impurity


The prior-art documents US7094781B2 and JMC, 2012, 55 (17), 7849-61 specifically 15 discloses the purification of compound of formula-1 by crystallization from methanol.
When carried out the prior-art process for the purification of compound of formula-1
by crystallization from methanol, the present inventors observed that the above specified
pyrimidine amine impurity and pyrimidine N-propyl impurity are not controlled within the
20 limits as suggested by ICH. In order to comply with the ICH limits, repeated purifications are
required which leads to loss in yield of around 20-25%.

In order to overcome the above problems, the present inventors have earnestly tried for various purification processes. After trying numerous solvents and purification techniques, the present inventors have surprisingly found that purification of compound of formula-1 using dichloromethane and methanol mixture has provided the compound with 5 excellent quality and higher yields with all the above mentioned impurities controlled well within the limits and in most of the cases in non-detectable levels which signifies that the process of the present invention is highly advantageous over the prior-art.
By developing the above described process for the purification of compound of 10 formula-1, the present inventors were able to get the desired compound in excellent yield and quality with all the impurities and residual solvents controlled well within the limits as defined by ICH and some of the impurities in non-detectable level.
The compound of formula-1 obtained by the above purification process is having 15 purity of greater than 99%, more preferably greater than 99.5%, most preferably greater than 99.9% by HPLC with all the impurities well within the limits.
All the above impurities were identified, characterized and well controlled within the limits as required by ICH guidelines.
20 The process developed by the present inventors is much efficient in terms of all the
parameters viz., cost-effectiveness and quality and consistently provides the required product with desired quality, impurity profile and with desired particle size.

a E
0 The third aspect of the present invention provides novel crystalline polymorph of N-
O
u
0 H
N'
N^X,
Formula-4 4a: X2= CI
HO'
Base

Macitentan Formula-1

N^^k

Br

Br

,AyOH
N.!::;o
Formula-5

Scheme-II:



Br
Br
Br .
OH

R-OH
Catalyst

O
r
OR FormuIa-6 6a: R= Me

\^
Dialkyl carbonate^ Base
o
O.
OR OR'
Formula-7 7a: R=R'= Me

N' ^X2
FormuIa-2 2a: X!=X2= CI

N T>H Forinula-8


Scheme-Ill:

0Y°,C//0 t-BuOH

CI

o
H FormuIa-9

*NH-
Base

O
H H Formula-10


H Formula-3
10
15

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.
Examples:
Example-l: Preparation of N-[5-(4-bromophenyl)-6-chloro-4-pyrimidinyl]-N'-propyI sulfamide (Formula-4a)
10
Potassium tert.butoxide (147 gm) was slowly added lot wise to a pre-cooled mixture of N-propylsulfamide compound of formula-3 (159 gm) and dimethyl -sulfoxide (500 ml) at 5-10°C and stirred the reaction mixture for 30 min at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 45 min at the same temperature. 5-(4-bromophenyl)-4,6-dichloropyrimidine compound of formula-2a (100 gm) was slowly added lot wise to the reaction mixture at 25-30°C and stirred the reaction mixture fori hr at the same temperature. Heated the reaction mixture to 45-50°C and stirred for 3 hrs
15 at the same temperature. Cooled the reaction mixture to 0-5°C, aqueous citric acid solution was slowly added and stirred for 30 min at the same temperature. Filtered the precipitated solid and washed with water. Isopropyl alcohol (500 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 75-80°C and stirred for 1 hr at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same
20 temperature. Filtered the solid, washed with isopropyl alcohol and then dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-1. Yield: 106.7 gm; M.R: 168-170°C; Purity by HPLC: 99.9%.
Example-2: Preparation of N-[5-(4-bromophenyl)-6-[2-hydroxyethoxy]-4-pyrimidinyl]-
25 N'-propylsuIfamide (Formula-5)

Potassium tert.butoxide (138 gm) was added to ethylene glycol (700 ml) at 25-30°C.
Heated the reaction mixture to 45-50°C and stirred for 1 hr at the same temperature. N-[5-(4-

Bromophenyl)-6-chloro-4-pyrimidinyl]-N'-propyl sulfamide compound of formula-4a (100
gm) was added to the reaction mixture at 45-50°C. Heated the reaction mixture to 95-100°C
30 and stirred for 35 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and
was added to pre-cooled aqueous citric acid solution at 5-10°C. Stirred the reaction mixture
15
3

for 15 min at 5-10°C. Filtered the precipitated solid and washed with water. Methanol (500 ml) and isopropyl alcohol (100 ml) were added to the obtained solid at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 2 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. Filtered the solid, washed 5 with isopropyl alcohol and dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-2. Yield: 85.0 gm; M.R: 108-110°C; Purity by HPLC: 99.5%.
Example-3: Preparation of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy] 10 ethoxyJ^-pyrimidinylJ-N'-propylsuIfamideO^ormula-l)
20
A. mixture of N-[5-(4-bromophenyl)-6-[2-hydroxyethoxy]-4-pyrimidinyl]-N,-propyl
sulfamide compound of formula-5 (100 gm), potassium tert.butoxide (130 gm) and toluene
(2000 ml) was stirred for 45. min at 25-30°C.. A solution of 5-bromo-2-chloropyrimidine (89.7
gm) in dimethylformamide (400 ml) was slowly added, to the reaction mixture at 25-30°C
15 and stirred for 6 hrs at the same temperature. Cooled the reaction mixture to 5-10°C and
aqueous citric acid solution was added to it. Raised the temperature of the reaction mixture to
25-30°C and stirred for 45 min at the same temperature. Both the organic and aqueous layers
were separated and washed the organic layer With water. Distilled off the solvent completely
from the organic layer under reduced pressure. Methanol (500 ml) was added to the obtained
compound at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 3 hrs at the
same temperature. Cooled the reaction mixture to 25-30bC and stirred for 2 hrs at the same
temperature. Filtered the precipitated solid, washed with methanol and"then dried the material to get the title compound.
Yield: 109.0 gm; Purity by HPLC: 98%.
o
Example-4: Preparation of N-[5-(4-bromophenyI)-6-[2-[(5-bromo-2-pyrimidinyl)oxy] ethoxy^-pyrimidinyll-N'-propylsulfamide (Formula-1)
Potassium tert.butoxide (117 gm) was added to a mixture of N-[5-(4-bromophenyl)-6-
[2-hydroxyethoxy]-4-pyrimidinyl]-N'-propylsulfamide compound of formula-5 (100 gm) and
30 tetrahydrofuran (1 L) at 25-30°C and stirred the reaction mixture for 45 min at the same
temperature. Dimethylformamide (200 ml) followed by 5-bromo-2-chloropyrimidine (89.7
I
)
gm) were added to the reaction mixture at 25-30°C and stirred for 6 hrs at the same temperature. Cooled the reaction mixture to 5-10°C and aqueous citric acid solution was slowly added to it. Raised the temperature of the reaction mixture to 25-30°C. Ethyl acetate was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. 5 Both the organic and aqueous layers were separated and washed the organic layer with water. Distilled off the solvent completely from the organic layer under reduced pressure. Methanol (500 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 2 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature; Filtered the precipitated5 solid and washed with
10 methanol. Dichloromethane (100 ml) was added to the obtained compound at 25^30°C. Heated the reaction mixture to reflux temperature. Methanol (1 L) was slowly added to the reaction mixture and stirred the reaction mixture at 60-65°C for 2 hrs. Cooled the reaction mixture to 0-5°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with methanol and then dried the material to get the title compound.
15 Yield: 68.0 gm.
Example-5: Preparation of 2-(5-bromopyrimidin-2-yloxy)ethanol
A mixture of ethylene glycol (70 gm) and potassium tert.butoxide (23 gm) was heated
to 60-65°C and stirred for 45 min at the same temperature. Dimethylformamide (20 ml) was
20 added to the reaction mixture at 60-65°C. Cooled the reaction mixture to 25-30°C. 5-bromo-
2-chloropyrimidine (10 gm) was added to the reaction mixture at 25-30°C and stirred for 6
hrs at the same temperature. Cooled the reaction mixture to 5-10°C and aqueous citric acid
ij solution was slowly added to it. Filtered the precipitated solid and washed with water to get
o o
£ the title compound.
25 Yield: 8.5 gm.

Example-6: Preparation of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]

iU
ethoxyl^-pyrimidinyll-N^propylsulfamideO^ormula-l)
A mixture of N-[5-(4-bromophenyl)-6-chloro-4-pyrimidinyl]-N'-propylsulfamide
30 compound of formula-4a (10 gm), potassium tert.butoxide (11 gm) and tert.butanol (100 ml)
was heated to 80-85°C and stirred the reaction mixture for 45 min at the same temperature. 2-

(5-bromopyrimidin-2-yloxy)ethanol (10.8 gm) was slowly added to the reaction mixture at 80-85°C and stirred for 6 hrs at the same temperature. Cooled the reaction mixture to 5-10°C and aqueous citric acid solution was slowly added to it. Raised the temperature of the reaction mixture to 25-30°C, ethyl acetate was added and stirred the reaction mixture for 15 5 min at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure. Methanol (50 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 2 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with 10 methanol and then dried the material to get the title compound. Yield: 10.9 gm.
Example-7: Purification of N-[5-(4-bromophenyI)-6-[2-[(5-bromo-2-pyrimidinyl)oxy] ethoxy]-4-pyrimidinyl]-N,-propylsuIfamide(Formula-l)
15 N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy.]ethoxy]-4-pyrimidinyl]-N*-
a
E o
C O
propylsulfamide compound of formula-1 (50 gm) was added to dichloromethane (300 ml) at 25-30°C and stirred the reaction mixture for 5 min at the same temperature. Charcoal (5 gm) was added to the reaction mixture'at 25-30°C and stirred for 30 min at the same temperature. Faltered the reaction mixture through hyflow bed and washed the hyflow bed with 20 dichloromethane. Distilled off 90% of the solvent from the filtrate under reduced pressure. Methanol (500 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 30 min at the same temperature. Filtered the precipitated solid, washed with methanol and then dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in fig-3. 25 Yield: 45.0 gm; Purity by HPLC: 99.9%.
Chloro bromo pyrimidine impurity: Not detected; Chloro impurity: Not detected; Ethylene
jjj hydroxy impurity: Not detected; Highest individual unspecified impurity: 0.02%.
Particle size distribution: D(0.1): 2.49 urn; D(0.5): 9.29 urn; D(0.9): 32.95 urn.
30
■ ■
18

Example-8: Preparation of N-[5-(4-bromophenyI)-6-chloro-4-pyrimidinyI]-N,-propyl sulfamide (FormuIa-4a)
Potassium tert.butoxide (37.5 Kg) was slowly added lot wise to a pre-cooled mixture of N-propylsulfamide compound of formula-3 (39.78 Kg) and dimethyl sulfoxide (125 Lt) at 5 5-10°C and stirred the reaction mixture for 30 min at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 45 min at the same temperature. 5-(4-bromophenyl)-4,6-dichloropyrimidine compound of formula-2a (25 Kg) was slowly added lot wise to the reaction mixture at 25-30°C and stirred the reaction mixture for 1 hr at the same temperature/Heated the reaction mixture to 55-60?C and stirred for 2 hrs
10 at the same temperature. Cooled the reaction mixture to 0-5°C, aqueous citric acid solution was slowly added to it and stirred for 15 min at the same temperature. Filtered the precipitated solid, washed with chilled water and spin dried the material. The obtained compound was added to isopropyl alcohol (125 Lt) at 25-3t)0C. Heated the reaction mixture to 80-85°C and stirred for 2 hrs at the'same temperature. Cooled the reaction mixture to 25-
15 30°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid, washed
with isopropyl alcohol and then dried the material to get the title compound.
Yield: 20.1 Kg. : .: .
Example-9: Preparation of N-[5-(4-bromophenyl)-6-[2-hydroxyethoxy]-4-pyrimidinyl]-20 N'-propylsulfamide (FormuIa-5)
Potassium tert.butoxide (27.6 Kg) was added to ethylene glycol (140 Lt) at 25-30°C.
Heated the reaction mixture to 45-50°C and stirred for 1 hr at the same temperature.
Compound of formula-4a (20 Kg) was added to the reaction mixture at 45-50°C. Heated the
| reaction mixture to 100-105°C and stirred for 33 hrs at the same temperature. Cooled the
25 reaction mixture to 25-30°C and was added to pre-cooled aqueous citric acid solution at 5-
^ 10°C and stirred for 15 min at same temperature. Filtered the precipitated solid, washed with
chilled water and then dried the material. Methanol (30 Lt) and isopropyl alcohol (60 Lt) were added to the obtained solid at 25-30°C. Heated the reaction mixture to 65-70°C and stirred for 2 hrs at the same temperature. Cooled the,reaction mixture to 25-30°C and stirred 30 for 3 hrs at the same temperatuie. Filtered the solid, washed with isopropyl alcohol and dried to get title compound. Yield: 14.8 Kg.
19
3

Example-10: Preparation of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy] ethoxy]-4-pyrimidinyI]-Nf-propylsuIfamide(Formula-l)
A mixture of N-[5-(4-bromophenyl)-6-[2-hydroxyethoxy]-4-pyrimidinyl]-N'-propyl sulfamide compound of formula-5 (15 Kg), potassium tert.butoxide (17.6 Kg) and 5 tetrahydrofuran (150 Lt) was stirred for 45 min at 25-30°C. Dimethylformamide (30 Lt) and 5-bromo-2-chloropyrimidine (13.5 Kg) were added to the reaction mixture at 25-30°C and stirred for 3 hrs at the same temperature. Cooled the reaction mixture to 5-10°C and aqueous citric acid solution was slowly added to it. Raised the temperature of the reaction mixture to 25-30°C,-ethyl acetate was added to it arid stirred for 15 min at the same temperature. Both 10 the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure. Methanol (30 Lt) was added to the obtained compound at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with methanol and spin dried the material. The obtained solid was added to dichloromethane (90 Lt) at 25-30°C. Charcoal (4.5 kg) was
15 added to the reaction mixture at 25-30°C and stirred the reaction mixture for 45 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with dichloromethane. Distilled off the solvent completely from the filtrate under reduced pressure. Methanol (120 Lt) was added to the obtained compound at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred for 1 hr at the same temperature. Filtered the
20 solid, washed with methanol and spin dried the material. The obtained solid was added to dichloromethane (23 Lt) at 25-30°C. Heated the reaction mixture to 35-40°C and methanol (150 Lt) was slowly added to it. Heated the reaction mixture to 60-65°C and stirred for 30 min at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid, washed with methanol and spin dried the
25 material. The obtained solid was added to dichloromethane (23 Lt) at 25-30°C. Heated the reaction mixture to 35-40°C and methanol (150 Lt) was slowly added to it. Heated the reaction mixture to 60-65°C and stirred for 30 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid, washed with methanol and spin dried the material. The obtained solid was
30 added to dichloromethane (23 Lt) at 25-30°C. Heated the reaction mixture to 35-40°C and
20

methanol (150 Lt) was slowly added to it. Heated the reaction mixture to 60-65°C and stirred for 30 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid, washed with methanol and dried the material to get the title compound. 5 Yield: 10.2 Kg.
Example-ll: Purification of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy] ethoxyl^-pyrimidinyll-N'-propylsulfamideO^ormula-l)
, N-[5 -(4-bromophenyl)-6- [2- [(5 :bromo72-pyrimidiny l)oxy]ethoxy] T^pyrimidinyl] -N'-, 10 propylsulfamide compound of formula-1 (10 Kg) was added to dichloromethane (60 Lt) at 25-3.0°C. Charcoal (3 Kg) was added to the reaction,mixture at 25-30°C and stirred for 45 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with dichloromethane. Distilled off the solvent completely from the filtrate under reduced pressure. Dichloromethane (15 Lt) was added to the obtained compound at 25-
15 30°C. Heated the reaction mixture to 35-40°C and methanol (100 Lt) was slowly added to it. Heated the reaction mixture to 60-65°C and stirred for 30 min at the same temperature. Cooled the reaction mixture to 0r5°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid, washed with methanol and then dried the material to get pure title compound. The PXRD pattern of the obtained compound is similar to figure-3.
20 Yield: 7.8 Kg; Purity by HPLC: 99.98%; Water content by KFR: 0.1% w/w. Related substances by HPLC:
_0) Q.
E o o
o
Ethylene hydroxy impurity: Not detected; Pyrimidine amine impurity: Not detected;
Pyrimidine N-propyl impurity: Not detected; Dimer impurity:'Not detected; Highest
| individual unspecified impurity: 0.01%; Total impurities: 0.02%.
25 Particle size distribution: D(0.1) is 0.67 urn, D(0.5) is 2.08 urn and D(0.9) is 4.16 urn.

g Example-12: Preparation of N-[5-(4-bromophenyl)-6-chIoro-4-pyrimidinyl]-N,-propyI
sulfamide (Formula-4a)
Potassium tert.butoxide (150 gm) was slowly added lot wise to a pre-cooled mixture
30 of N-propylsulfamide compound of formula-3 (159.1 gm) and dimethyl sulfoxide (500 ml) at
5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 45 min at

■
the same temperature. 5-(4-bromophenyl)-4,6-dichloropyrimidine compound of formula-2a (100 gm) was slowly added lot wise to the reaction mixture at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 3 hrs at the same temperature. Cooled the reaction mixture to 0-5 °C, aqueous citric acid solution was slowly added and stirred for 20 min at the same temperature. Filtered the precipitated solid and washed with water. Isopropyl alcohol (500 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with
isopropyl alcohol arid then dried the material to get the title compound. Yield: 118 grii; M.R: 168.2-169.3°C.
Example-13: Preparation of N-[5-(4-bromophenyl)-6-[2-hydroxyethoxy]-4-pyrimidinyI]-N'-propylsuIfamide(Formula-5)
. Potassium.tert.butoxide (138 gm) was-added.to ethylene glycol (700 ml) at 25-30°C. Heated the reaction mixture to 45-50°C and stirred for 1 hr at thesame temperature. N-[5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl]-N,-propylsulfamide compound of formula-4a (100 gm) was added to the reaction mixture at 45-50°C. Heated the reaction mixture to 80-85°C and stirred for 35 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and was slowly added to pre-cooled aqueous citric acid solution at 5-10°C. Stirred the reaction mixture for 20 min at 5-10°C. Filtered the precipitated solid and washed with water. Water (500 ml) was added to the obtained solid at 25-30°C and stirred the reaction mixture for 2 hrs at the same temperature. Filtered the solid, washed with water and dried the material to get the title compound.
Yield: 100 gm; M.R: 108-112°C. -
Example-14: Preparation of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy] ethoxy]-4-pyrimidinyl]-Nf-propyIsulfamide(Formula-l)
Dimethylformamide (150 ml) and 5-bromo-2-chloropyrimidine (67.3 gm) were added to a mixture of N-[5-(4-bromophenyl)-6-[2-hydroxyethoxy]-4-pyrimidinyl]-N'-propyl sulfamide compound of formula-5 (75 gm) and tetrahydrofuran (750 ml) at 25-30°C. Cooled the reaction mixture to 10-15°C. Potassium tert.butoxide (87.8 gm) was slowly added lot
22

10
wise to the reaction mixture at 10-15°C. Raised the temperature of the reaction mixture to 25-30° and stirred for 4 hrs at the same temperature. Cooled the reaction mixture to 0-5°C and aqueous citric acid solution was slowly added to it. Raised the temperature of the reaction mixture to 25-30°C. Extracted the reaction mixture with ethyl acetate and distilled off the solvent completely from the organic layer under reduced pressure. Methanol (150 ml) was added to the obtained compound at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with methanol. Dichloromethane (450 ml) was added to the obtained solid at 25-30°C. Charcoal (22.5 gm) was added to the reaction mixture at 25-30°C and stirred for 30 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with dichloromethane. Distilled off the solvent completely from the filtrate under reduced pressure. Methanol (600 ml) was added to the obtained compound at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred for 1 hr at the same temperature. Filtered the solid, washed with methanol*. Dichloromethane (112.5 ml) was added to the obtained compound at 15 25-30°C. Heated the reaction mixture to reflux temperature and 50% of the solvent was distilled off. Methanol (750 ml) was added to the reaction mixture and continued the distillation process. Slowly cooled the reaction mixture to 0-5°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with methanol and dried the material to get the title compound. Yield: 60.0 gm; M.R: 135-138°C. 20
Example-15: Purification of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyI)oxy] ethoxy]-4-pyrimidinyl]-N'-propylsulfamide(FormuIa-l)
25
Charcoal (26.4 gm) was added to a mixture of compound of formula-1 (88 gm) and
dichloromethane (528 ml) at 25-30°C and stirred the reaction mixture for 45 min at the same
temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed
with dichloromethane. Distilled off 70% of the solvent from the filtrate. Methanol (880 ml) was added to the reaction mixture and continued the distillation process. Slowly cooled the

700131063
, 700131063
m
We Claim:
1. A process for the purification of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)
oxy]ethoxy]-4-pyrimidinyl]-N'-propyl sulfamide compound of formula-1, comprising of;
a) Dissolving the compound of formula-1 in a suitable solvent,
5 b) optionally treating the reaction mixture with charcoal,
c) slowly adding a suitable anti-solvent to the solution to provide pure compound of formula-1.
2.* The process according to claim 1, wherein
10 in step-a).the suitable solvent is selected from chloro solvents, cyclic ether
solvents, polar-aprotic solvents, ester solvents, ketone solvents or their mixtures; preferably chloro solvent;
in step-c) the suitable anti-solvent is selected from alcohol solvents, polar solvents, hydrocarbon solvents or their mixtures; preferably an alcohol solvent.
15
3. The process according to claim 1, wherein step-c) further comprises heating the reaction
mixture to a suitable temperature ranges from 30°C to 120°C and then cooling to a
suitable temperature ranges from 30°C to -30°C.
20 4. A process for the purification of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl) oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide compound of formula-1, comprising of;
a) Dissolving the compound of formula-1 in dichloromethane,
b) optionally treating the reaction mixture with charcoal,
c) slowly adding methanol to the reaction mixture,
25 d) optionally heating and cooling the reaction mixture to provide pure compound of
formula-1.
« 5. A process for the purification of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)
o
£ oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide compound of formula-1, comprising of;
o
CN
30 a) Dissolving the compound of formula-1 in dichloromethane,
CO CO CO
b) optionally treating the reaction mixture with charcoal,
c) partially distilling off the solvent from the reaction mixture,
24
CM
CO
to

d) adding methanol to the reaction mixture,
e) continuation of the distillation process and heating the reaction mixture to 60-65 °C,
f) cooling the reaction mixture to precipitate pure compound of formula-1 as a solid.
5
6. Crystalline polymorph of N-[5-(4-bromophenyl)-6-chloro-4-pyrimidinyl]-N,-propyl
sulfamide compound of formula-4a characterized by its PXRD pattern having peaks at
6.9, 14.0, 16.3, 18.1, 20.2, 20.8, 22.5, 22.8, 23.5, 24.5, 24.7, 27.5 and 28.3 ± 0.2° of 20.
7. Crystalline polymorph of N-[5-(4-bromophenyl)-6-[2-hydroxyethoxy]-4-pyrimidinyl]-N,-
10 propyisulfamide compound of formula-5 characterized by its PXRD pattern having peaks
at 10.7, 12.7, 14.4, 16.0, 16.7, 17.7, 19.7, 21.6, 24.3, 26.4, 284 and 33.9 ± 0.2° of 20.
8. A process for the preparation of N-propyl sulfamide compound of formula-3,
■■■■•■■■■■ ,N^>-N ' NH2
H 2
1 5 Formula-3
comprising of, reacting the tert-butyl N-propylsulfamoyl carbamate compound of
formula-10,


H H
CW^O

£

Formula-10
20 with a suitable deprotecting agent optionally in a suitable solvent to provide compound of
formula-3 provided that the deprotecting agent is not HCl in dioxane.
9. The process according to claim 8, wherein the suitable deprotecting agent is selected
from acids such as HCl, HBr, formic acid, acetic acid, trifluoroacetic acid, aikyl/aryl
25 sulfonic acids; acetyl chloride in presence of alcohol solvent, trialkylsilyl halide,
tetrabutyl ammonium fluoride, eerie ammonium nitrate and HCl is used in the form of EtOAc-HCl, methanol-HCl, ethanol-HCl, isopropyl alcohol-HCl, aq.HCl, conc.HCl or HCl gas.

25

10. A process for the preparation of N-propyl sulfamide compound of formula-3, comprising of reacting the tert-butyl N-propylsulfamoyl carbamate compound of formula-10 with HCl in ethyl acetate to provide compound of formula-3.
Dated this day 1^iyy of August 2016.
10

15 Authorized Signatory
(Srinivasan Thirumalai Rajan)
MSN Laboratories Private Limited